Potent inhibitions of monoamine oxidase A and B by acacetin and its 7-O-(6-O-malonylglucoside) derivative from Agastache rugosa

Abstract Five compounds were isolated from the leaves of Agastache rugosa and tested for monoamine oxidase (MAO) inhibitory activity. Acacetin, a flavonoid, potently inhibited recombinant human MAO-A and MAO-B (IC 50  = 0.19 and 0.17 μM, respectively), and reversibly and competitively inhibited MAO-A and MAO-B (K i  = 0.045 and 0.037 μM, respectively). Acacetin 7- O -(6- O -malonylglucoside) (AMG) was also found to effectively inhibit MAO-A and MAO-B (IC 50  = 2.34 and 1.87 μM, respectively), and to reversibly and competitively inhibit MAO-A and MAO-B (K i  = 1.06 and 0.38 μM, respectively). Tilianin (a glucoside derivative of acacetin) had little inhibitory activity, but the introduction of a malonyl group at sugar moiety significantly increased inhibitory activity. Molecular docking simulation revealed the binding energy of acacetin for MAO-B (−44.2 kcal/mol) was greater than its energy for MAO-A (−27.0 kcal/mol), and that the Cys172 residue of MAO-B was important for hydrogen bonding with acacetin. AMG was predicted to bind to MAO-B with an energy of −23.1 kcal/mol by possible hydrogen-bond formation between an oxygen atom of Ile477 residue and a hydrogen atom (H17) of AMG. However, the interaction between AMG and MAO-A was not verified by the docking simulation. This study suggests acacetin and AMG be viewed as new reversible MAO inhibitors, and useful lead compounds for the inhibitor development.